Combination therapy with Fasudil and Sildenafil ameliorates monocrotaline-induced pulmonary hypertension and survival in rats

Md Elias-Al-Mamun, Kimio Satoh, Shin Ichi Tanaka, Toru Shimizu, Suvd Nergui, Satoshi Miyata, Yoshihiro Fukumoto, Hiroaki Shimokawa

研究成果: Article査読

抄録

Background: Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary artery (PA) remodeling, elevated PA pressure and right ventricular (RV) failure. It has been previously demonstrated that treatment with a Rho-kinase inhibitor, fasudil, ameliorates PH in animal models. Here, whether combination therapy with fasudil and sildenafil further ameliorates PH in rats was examined. Methods and Results: PH was induced in Sprague-Dawley rats by the use of a single subcutaneous monocrotaline (MCT) injection, which caused PA remodeling, elevated RV systolic pressure (RVSP), and RV hypertrophy (RVH). While fasudil and sildenafil monotherapy inhibited the development of MCT-induced PH in the prevention and treatment protocols, their combination therapy further improved RVSP and RVH. Moreover, a histological examination demonstrated significant improvements of PA remodeling in the combination group compared with the monotherapy groups. An echocardiographic examination also revealed significant reduction in RV diameter in the combination group compared with the monotherapy groups. Mechanistic experiments revealed significant inhibition of Rho-kinase activity in PA trunk, lung and RV tissues in the combination group as well as in the monotherapy groups. Finally, the combination therapy markedly improved the long-term survival compared with the monotherapy groups. Conclusions: These results indicate that the combination therapy with fasudil and sildenafil shows the synergistic effects through the inhibition of Rho-kinase activity for the treatment of PH.

本文言語English
ページ(範囲)967-976
ページ数10
ジャーナルCirculation Journal
78
4
DOI
出版ステータスPublished - 2014 1 1

ASJC Scopus subject areas

  • 循環器および心血管医学

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